ofirnoflast (HT-6184) / Halia Therap - LARVOL DELTA

TP53 exon 7 (c.742C>T; p. Arg248Trp) vaf suppression by novel oral allosteric NEK7 inhibitor in a patient with low-risk myelodysplastic syndrome in A phase 2 clinical trial (ASH 2025) - P2 | "Ofirnoflast (HT-6184) is an oral, first-in-class allosteric inhibitor of NEK7 currently under evaluation in a Phase 2 trial in patients with low-risk MDS and symptomatic anemia (NCT07052006)...These findings suggest that ofirnoflast may restore endogenous anti-clonal immunity through inhibition of inflammasome signaling. Further evaluation in larger TP53-mutant MDS cohorts is warranted to confirm these preliminary observations and assess the potential of ofirnoflast as a targeted, immune-modulating therapy."

Clinical • P2 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • NLRP3 • TP53

The novel allosteric NEK7 inhibitor ofirnoflast (HT-6184) demonstrates robust and sustained hematologic response in subjects with IPSS-R very low, low or intermediate risk myelodysplastic syndrome (MDS) and symptomatic anemia (ASH 2025) - P2 | "Importantly, ofirnoflast supported sustained 32-week HI-E in difficult-to-treat ESA-refractory and ESA-intolerant populations. With a robust HI-E rate, favorable safety profile, absence of myelosuppression, arelevant and targeted mechanism of action, ofirnoflast offers a novel oral alternative that eases theburden of current treatments in a diverse MDS population."

Clinical • Anemia • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • CASP1 • GATA1 • IL1B • NLRP3 • SF3B1

Ofirnoflast suppresses heme-induced inflammation, representing a novel therapeutic strategy for hemolytic anemias (ASH 2025) - "Inhibition of the NLRP3inflammasome has been shown to mitigate inflammation and cell death in preclinical models ofhemolytic anemia.Ofirnoflast (HT-6184) is a novel, orally bioavailable small molecule that selectively inhibits NLRP3inflammasome activation by allosteric modulation of Nek7, a critical scaffolding protein forinflammasome assembly...Ofirnoflast potently inhibits heme-induced activation of the NLRP3 inflammasome in vitro,reducing both inflammatory cytokine release and pyroptotic markers. These findings supportcontinued investigation of Ofirnoflast as a promising therapeutic approach in sickle cell diseaseand other hemolytic anemias characterized by NLRP3-mediated inflammation."

Anemia • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease • CASP1 • IL1B • NLRP3

The novel allosteric NEK7 inhibit ofirnoflast (HT-6184) reduces oxidized mitochondrial DNA in patients with low-risk myelodysplastic syndrome (ASH 2025) - P2 | "Notably, some patients with substantial reductions in ox‑mtDNA did not meethematologic response criteria, suggesting that absolute ox‑mtDNA levels may be more clinically relevantthan percent change alone. These findings support further evaluation of alternative dosing, schedules,and treatment durations to determine whether achieving lower circulating ox‑mtDNA concentrationsmay enhance the likelihood of hematologic response in patients with low-risk MDS."

Clinical • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • NLRP3

The novel allosteric NEK7 inhibitor ofirnoflast (HT-6184) suppresses IL-8 and other pro-inflammatory cytokines in patients with low-risk myelodysplastic syndrome and symptomatic anemia (ASH 2025) - P2 | "These findings support further evaluation of inflammasome modulation as apotential strategy to improve hematopoiesis in LR‑MDS. Additionally, Larger studies with expandedsampling will clarify the therapeutic relevance of cytokine reduction in LR-MDS."

Clinical • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CXCL8 • IL18 • IL1B • IL6 • NLRP3 • TNFA

Targeting NLRP3 with ofirnoflast, alone or in combination with semaglutide, ameliorates inflammatory anemia associated with obesity-induced inflammation in rodent models (ASH 2025) - "Ofirnoflast (HT-6184) is aselective, orally available NLRP3 inflammasome inhibitor that targets the Nek7 scaffold protein.This study evaluated the therapeutic potential of Ofirnoflast, alone or in combination with theGLP-1 receptor agonist semaglutide, in restoring hematologic function in diet-induced obesemice.Objective:To determine whether pharmacologic inhibition of the NLRP3 inflammasome with Ofirnoflast,alone or in combination with the GLP-1 agonist semaglutide, can prevent or reverse obesity-associated inflammatory anemia in a preclinical diet-induced obese mouse model.Male C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks to induce obesity and randomizedinto four groups: HFD control, semaglutide (0.03 mg/kg), Ofirnoflast (5 mg/kg), and Ofirnoflast +semaglutide...Obesity-associated anemia of inflammation is driven in part by NLRP3-mediated inflammatorysignaling. Pharmacologic inhibition of the NLRP3 inflammasome with Ofirnoflast reduced adiposeinflammation..."

Combination therapy • Preclinical • Anemia • Genetic Disorders • Hematological Disorders • Inflammation • Obesity • NLRP3

Ofirnoflast, a novel inflammasome inhibitor, rewires transcriptional programs and shows clinical and preclinical efficacy in myeloid neoplasms (ASH 2025) - P1 | "Furthermore, genetic ablationof IL1R1 in Tet2-mutant cells or pharmacologic inhibition of IL1R1 in primary MDS/CMML patient-derivedcells with Anakinra abrogated the anti-leukemic effects of ofirnoflast, indicating that its therapeuticactivity is primarily mediated through suppression of chronic inflammation driven by the IL-1β/IL1R1 axis.In vivo, ofirnoflast treatment reduced leukemic burden by ~3-fold in both MDS/AML (n = 5, P = 0.005) andCMML (n = 7–9, P = 0.04) patient-derived xenograft models. scRNA-seq of treated xenografts revealed adual mechanism of action: (1) suppression of inflammatory and proliferative signaling pathways (NF-κB,TNF, and cell cycle genes), and (2) induction of apoptosis and erythroid differentiation programs,corroborating both molecular and functional in vivo and in vitro findings.Translating these insights to the clinic, a Phase 1 trial (n = 64; NCT05447546) in healthy volunteersshowed that ofirnoflast significantly reduced serum levels..."

Preclinical • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CASP8 • CD34 • GATA1 • IL18 • IL1B • IL1R1 • IL6 • NLRP3 • PYCARD • TET2

Halia Therapeutics Announces Positive Phase 2a Data for Ofirnoflast in Lower-Risk MDS at ASH 2025 (PRNewswire) - "72% of patients (13/18) achieved HI-E at Week 16, with responders showing a median hemoglobin increase of 3.5 g/dL. Strong activity in difficult-to-treat patients, including 91% HI-E in ESA-refractory and 75% HI-E in ESA-intolerant subjects. Consistent responses across disease biology, with HI-E observed across transfusion burden categories, WHO morphologic subtypes, and major mutation groups (SF3B1, TET2, DNMT3A, ASXL1, TP53)....Halia is finalizing the dataset and preparing to initiate a global Phase 3 pivotal trial in early 2026."

New P3 trial • P2a data • Myelodysplastic Syndrome

Ex-Vivo Human Whole Blood Assay for Evaluating the Pharmacodynamics of HT-6184: Reduction in NLRP3 Inflammasome Mediated Cytokine Production (ASH 2023) - "In addition, this assay has the potential to be used to measure the pharmacodynamic properties and the efficacy of HT-6184 and other inflammasome inhibitors in future healthy volunteer clinical trials. In conclusion, this study highlights the importance of innovative and physiologically relevant assay systems in identifying and evaluating potential therapeutic agents for inflammatory diseases."

PK/PD data • Preclinical • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • IL18 • IL1B • IL6 • NLRP3 • TNFA

HT-6184 Inhibits the Formation of the NLRP3 Inflammasome in Human Monocytic THP-1 Cells (ASH 2023) - "Since THP-1 cells are a monocytic cell line, this data suggests our ability to inhibit the NLRP3 pathway in hematological disorders effectively. By preventing inflammasome formation and activation, we expect to be able to reduce disease burden in hematological diseases."

Hematological Disorders • GLI2 • IL18 • IL1B • NLRP3

Modulation of NLRP3 Inflammasome in Monocytes By HT-6184 in a Single-Cell Proteomic Study (ASH 2023) - "Further research should explore the characteristics of HT-6184 and its ability to modulate the inflammasome in diverse in vitro and in vivo models. The modulation of the NLRP3 inflammasome by HT-6184 holds potential therapeutic implications for managing inflammatory disorders associated with dysregulated NLRP3 activation."

CNS Disorders • Immunology • Infectious Disease • Inflammation • Metabolic Disorders • CXCL8 • IL18 • IL1B • NLRP3 • TNFA

Halia Therapeutics to Present Groundbreaking Data on Novel Allosteric NEK7 Inhibitor Ofirnoflast at the 2025 American Society of Hematology Annual Meeting (PRNewswire) - "The presentations will feature comprehensive clinical...data on orfinoflast (HT-6184), a novel allosteric NEK7 inhibitor targeting the NLRP3 inflammasome, demonstrating its potential across multiple hematologic conditions, including myelodysplastic syndrome, hemolytic anemias, and inflammatory conditions. Clinical data from the ongoing study of orfinoflast demonstrate robust and sustained hematologic responses in patients with IPSS-R very low, low, or intermediate risk myelodysplastic syndrome (MDS) and symptomatic anemia."

Clinical data • Anemia • Myelodysplastic Syndrome

Preclinical studies presented at ASH showcase ofirnoflast's broader therapeutic potential, including its ability to suppress heme-induced inflammation, representing a novel therapeutic strategy for hemolytic anemias (PRNewswire) - "Additional research demonstrates that targeting NLRP3 with ofirnoflast, alone or in combination with semaglutide, ameliorates inflammatory anemia associated with obesity-induced inflammation in rodent models."

Preclinical • Anemia • Obesity

Halia Therapeutics, Inc…announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to its investigational medicine ofirnoflast (HT-6184) for the treatment of Myelodysplastic Syndromes (MDS) (PRNewswire) - "Ofirnoflast is a selective NEK7 allosteric modulator designed to prevent the formation and promote the disassembly of the NLRP3 inflammasome, a central driver of chronic inflammation in multiple diseases. In MDS, inflammasome activation is increasingly recognized as a key contributor to ineffective hematopoiesis and bone marrow failure."

Orphan drug • Myelodysplastic Syndrome

A Ph2 Study to Evaluate the Safety, Efficacy and Tolerability of HT-6184 and Semaglutide in Obese Participants With T2DM (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Halia Therapeutics, Inc.

New P2 trial • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Ofirnoflast: A First-in-Class NEK7-Targeted Inhibitor of the NLRP3 Inflammasome. (PubMed, J Drug Target) - "In a DSS-induced colitis model, treatment significantly reduces cytokine levels and improves clinical and histopathological outcomes. These data identify NEK7 as a novel, druggable target in NLRP3 inflammasome signaling and support ofirnoflast's potential as a differentiated therapeutic agent for certain chronic inflammatory diseases."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Targeted Protein Degradation • IL1B • NLRP3

A Phase 2a Study of HT-6184 in Subjects With MDS (clinicaltrials.gov) - P2 | N=37 | Active, not recruiting | Sponsor: Halia Therapeutics, Inc.

New P2 trial • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Halia Therapeutics Completes Enrollment in Phase 2a Clinical Trial of HT-6184 for Myelodysplastic Syndrome (MDS) (PRNewswire) - "Halia Therapeutics...announced the completion of enrollment for its open-label Phase 2a clinical trial evaluating HT-6184 (Ofirnoflast) in patients with lower-risk Myelodysplastic Syndrome (MDS) who are refractory to, intolerant of, or ineligible for erythropoiesis-stimulating agents (ESA). The study (CTRI/2023/11/059758) is designed to evaluate the efficacy, safety, and biomarker response of HT-6184, a novel allosteric modulator of NEK7 that disrupts NEK7–NLRP3 protein interaction, thereby preventing the formation of the NLRP3 inflammasome....The two-stage study enrolled 18 evaluable patients in Stage 1 and has now completed enrollment of an additional 15 participants in Stage 2....An interim analysis was conducted following Stage 1, and topline results from the complete study are expected later this year."

Enrollment closed • P2a data • Myelodysplastic Syndrome

Halia Therapeutics Awarded Novo Nordisk Golden Ticket to Advance Obesity and Inflammation Research (PRNewswire) - "The Novo Nordisk Golden Ticket – BioLabs European Award is granted to promising biotech companies working on transformational therapies in cardiometabolic and obesity-related diseases...'With access to BioLabs' premier facilities and mentorship from Novo Nordisk, we are in a stronger position to advance HT-6184 toward clinical development.'....The company is preparing to initiate a Phase 2 clinical study in combination with Semaglutide in early 2025."

Commercial • New P2 trial • Inflammation • Obesity

Halia Therapeutics to Attend the 43rd J.P. Morgan Healthcare Conference and Present at BioPharma Obesity Innovation Forum in San Francisco (PRNewswire) - "At The BioPharma Obesity Innovation Forum, Dave J. Bearss, Ph.D., President and CEO of Halia will be presenting data on its lead candidate, HT-6184, the first drug to target the protein NEK7 to inhibit NLRP3 inflammasome activity to resolve chronic inflammation for treating multiple diseases including the chronic inflammatory effects of obesity."

Clinical data • Inflammation • Obesity

Halia Therapeutics Announces Positive Topline Data and Advances to Second Stage of Phase 2 Clinical Trial for HT-6184 in Patients with Low-Risk Myelodysplastic Syndromes (LR-MDS) (PRNewswire) - P2 | N=40 | "The initial cohort of 18 patients with LR-MDS demonstrated a hematological improvement-erythroid (HI-E) response to HT-6184 treatment following 16 weeks of monotherapy, exceeding the preset requirement of at least three responders. Having achieved this critical milestone, the trial now advances to its second stage enrolling an additional 8-10 patients to further validate HT-6184's potential....The Phase 2 trial utilizes a Simon's minimax two-stage design to evaluate the safety and efficacy of HT-6184 in up to 40 patients across multiple clinical sites in India....The trial is expected to conclude by the end of Q2 2025. The results of this study are anticipated to provide pivotal data to support HT-6184's continued clinical development and eventual regulatory submission."

P2a data • Trial status • Myelodysplastic Syndrome

Halia Therapeutics to Attend Global Health Exhibition 2024 (PRNewswire) - "Halia Therapeutics will host an exhibition booth to showcase its efforts in targeting two indications, Alzheimer's disease and obesity. Halia's candidate HT-4253 is a LRRK2 inhibitor administered orally with excellent brain penetration. LRRK2 is a key modulator of neuroinflammation, which plays a critical role in neurodegenerative diseases. HT-6184 is a first-in-class, selective and orally bioavailable inhibitor of the NEK7/NLRP3 inflammasome. HT-6184 is being tested in combination with semaglutide to target inflammation, which has been linked to obesity-related metabolic dysfunction."

Clinical • Alzheimer's Disease • CNS Disorders • Inflammation • Obesity

Halia Therapeutics to Present Promising Data at Obesity Week 2024: HT-6184 Shows Enhanced and Sustained Weight Loss with GLP-1 Agonist Combination (PRNewswire) - "Halia Therapeutics...announced today that it will present promising data on HT-6184's potential to enhance and sustain weight loss when combined with semaglutide. This presentation will occur at the upcoming Obesity Week 2024 conference, scheduled for November 3-6, 2024, in San Antonio, TX....'Our findings indicate that this combination further increases weight loss compared to semaglutide treatment alone. HT-6184 has shown a unique ability to reshape the immune microenvironment in obese adipose tissue by modulating macrophage polarization. It shifts chronic inflammatory signaling towards a profile resembling lean adipose tissue, reducing pro-inflammatory M1 macrophage infiltration while promoting anti-inflammatory M2 macrophage expansion.'"

Preclinical • Immunology • Metabolic Disorders • Obesity

Evaluating Ability of HT-6184 to Reduce Inflammation and Pain After Third Molar Extraction (clinicaltrials.gov) - P2 | N=81 | Completed | Sponsor: Halia Therapeutics, Inc. | Recruiting ➔ Completed

Biomarker • Trial completion • Inflammation • Pain • CRP

TRIAL IN PROGRESS: PHASE II STUDY OF THE NLRP3 INFLAMMASOME & MYDDOSOME INHIBITOR HT-6184 IN PATIENTS WITH LOW OR INTERMEDIATE-RISK MYELODYSPLASTIC SYNDROME (MDS) (EHA 2024) - "From cycle 5 to cycle 8, dosing with epoetin alfa subcutaneously (SC) weekly or darbepoetin alpha SC every 2weeks is permitted in subjects not responding to HT-6184 monotherapy at week 16. This multi-center, Phase IIa clinical trial started enrollment and first patient treatment on 9 December 2023,with the study now active in 8 centers. Preliminary safety, efficacy, and biomarker outcomes data from HT-6184treatment will be presented"

Clinical • IO biomarker • P2 data • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • IL1B • IRAK1 • NLRP3